This program project grant is focused on the etiology and prevention of oral cancer. While tobacco and alcohol consumption are clearly the major risk factors for this disease, other factors such as diet are also clearly involved. The purpose of this proposal is to address important and unanswered questions regarding the etiology of oral cancer and to develop preventive strategies based on this information. A major strength of this research is its interdisciplinary, yet highly integrated design with projects areas including epidemiology, snuff carcinogenicity and toxicity, laboratory studies on chemoprevention and mechanism, and primary prevention studies involving health education in children. In addition, all research projects have are focused on an ultimate of cancer prevention. Some of the major areas being addressed include: the role of tobacco-specific carcinogens and toxicants in snuff carcinogenicity; the development of new model systems for testing potential chemopreventive agents; the efficacy of nutritionally-bound cocktails including Se-containing compounds as chemopreventive agents, and the role of glutathione depletion as a risk factor for oral cancer and a possible central mechanism for effects in alcohol consumption and nutrient deficiencies. The studies include a multi-disciplinary team of investigators with a long history of collaboration in the area of disease prevention. Altogether the results from these studies should provide key information on the prevention of oral cancers based upon a multi-dimensional approach of chemoprevention, early health education, and regulation of tobacco products.